There are several different drug delivery technologies that are utilized to treat disease. Conventional drug delivery methods typically result in the patient experiencing severe “peaks and valleys” in the plasma level of the therapeutic agent being administered, as well as often requiring multiple dosings per day.
These problems were addressed somewhat by the development of sustained release drug delivery products, where the patient experienced less severe plasma level “peaks and alleys” and there were reduced dosings per day. Subsequent development of controlled release drug delivery technologies provided for no “peaks and valleys” in the daily plasma level, as well as providing for a daily, weekly or monthly dosing regimen. Controlled release drug delivery systems can be designed to target a local area or the systemic circulation and can be administered in a variety of ways, including orally, transdermally, as an implant, by injections, and so forth.
Many methods of treating diseases in and originating in the orofacial environment, have involved oral administration of drugs such as anti-inflammatory or anti-infective agents, for example. However, such systemic therapies are often unable to reach the targeted diseased local area. In addition, patients can experience sub-therapeutic levels and/or fluctuating concentrations of agent with systemic therapies. Further, in order for such systemic administration to provide adequate drug levels to treat the orofacial tissue, the actual dosage administered often needs to be extremely high. As the systemic concentration is elevated, there is a greater likelihood of the patient experiencing systemic side-effects and even toxicity. Another problem with high-dosing therapies, particularly when administering anti-infective agents such as antibiotics, is the increase likelihood of bacterial resistance.
Other methods of treating orofacial diseases have involved topical applications and intra-oral products that are applied in the mouth or dental area on the surface of structures. Some formulations are placed within the periodontal pocket, others are on the mucous membrane or other surfaces, etc. Such formulations often include anti-infectives as it is often desirable to minimize or eliminate the bacteria present in the mouth while treating orofacial diseases such as periodontal disease. Examples of products that are positioned within the periodontal pocket include a tetracycline-containing ethylene/vinyl acetate copolymer that is positioned within the periodontal pocket (Actisite®, Proctor & Gamble); a chorhexidine gluconate-containing biodegradable hydrolyzed gelatin matrix (PerioChip®, Astra Pharmaceuticals); and a doxycycline-containing biodegradable polymer that is administered as a liquid and solidifies in situ to conform to the shape of the periodontal pocket (Atridox™, 8.5% doxycycline in the ATRIGEL® Delivery System, Atrix Laboratories, Inc.).
However, conventional and even the so-called advanced administration, including those involving the periodontal pocket have several limitations, ranging from low drug levels at the disease site and drug level fluctuation between applications to inconsistent patient compliance. And in the case of non-predetermined dosage forms, like for example the gel system, there is no assurance that any of the product has been placed properly into the pocket or spilled before or during application. Even when an attempt was made to place part of the product into the pocket, the dosage was not known. For these types of dosage forms there is no control over the accurate dosage amount and consequently over the delivery rate, negatively compounded by the fact that the final system can have variable shapes and surface areas, factors that critically influence drug delivery rates. In addition, besides being very clumsy to apply some products have to be manipulated before application (not ready-for-use right out of the storage system, e.g., multi-component systems that have to be mixed by the administrator before use) making the system prone to inappropriate handling, spilling and therefore having the potential for being non-therapeutic or not working as originally designed. But even when therapeutic agents are placed as directed within the oral cavity, the agent is subjected to wash-out or dilution due to the constant flow of saliva, crevicular fluid outflow from the periodontal pocket, as well as the patient's intake of food and beverages, all of which affect/minimize/reduce the amount of agent that is able to effectively treat the oral disease.
Another limitation with conventional administration is that the selection of therapeutic agents is somewhat limited to those that are less potent, to prevent toxicity. Based on thermodynamic reasons, very high systemic concentration levels (so high that they may cause systemic toxicity), are often required to drive the drug into the localized diseased area in an attempt to establish the therapeutic concentration level in the targeted tissue. Therefore, only therapeutic agents that have a large therapeutic index and are not too expensive, find utilization in conventional therapy. Active agents that may be more effective but are associated with toxicity or are very costly to administer in high doses, can not be used in the state of the art methodologies.
Accordingly, there is a continuing need to find improved methods for treating orofacial diseases that will overcome some or all of the shortcomings of the art, as well as present new methodologies for administering a wider range of therapeutic agents. The present invention addresses those needs by means of an implantable or insertable controlled release drug delivery system that is positioned within the diseased orofacial tissue and provides a uniform concentration of therapeutic agent at the target tissue site.